U.S. Pat. No. 4,536,518, which is herein incorporated by reference, disclosed cis-isomeric derivatives of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine and their pharmaceutically acceptable salts. These compounds act to block the synaptosomal uptake of serotonin (5-hydroxy-tryptamine), thereby alleviating serotonin abnormalities at central receptor sites. Among them sertraline hydrochloride, chemically (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride is a selective serotonin reuptake inhibitor (SSRI). Sertraline hydrochloride is represented by the following structure:

Sertraline hydrochloride can exist in different crystalline forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
Processes for the preparations of sertraline, its pharmaceutically acceptable salts and related compounds were described in U.S. Pat. No. 4,536,518 (Pfizer Inc.). U.S. Pat. No. 4,536,518 described a process for preparation of sertraline hydrochloride by treating an ethyl acetate/ether solution of sertraline free base with gaseous hydrogen chloride.
U.S. Pat. No. 5,248,699 (Pfizer Inc.) described five crystalline forms of sertraline hydrochloride (Forms I, II, III, IV and V), and characterizes them by single crystal x-ray analysis, powder x-ray diffraction, infra-red spectroscopy, and differential scanning calorimetry. U.S. Pat. No. 5,248,699 further described that the synthetic procedure described and exemplified in U.S. Pat. No. 4,536,518 produces the sertraline hydrochloride crystalline form designated herein as Form II. The patent also reported that form II is produced by rapid crystallization of sertraline hydrochloride from an organic solvent, including isopropyl alcohol, hexane, generally describes methods for making sertraline hydrochloride forms I to V. According to this patent, the preferential formation of Forms I, II or IV in an acidic solution consisting of isopropyl alcohol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid and ethyl acetate depends on the rapidity of crystallization.
U.S. Pat. No. 5,734,083 (Torcan Chemical Ltd.) discloses a polymorphic form of sertraline hydrochloride (T1), together with the process of preparation.
U.S. Pat. No. 6,495,721 (Teva Pharm. Ind.) describes various polymorphic forms of sertraline hydrochloride such as, crystalline forms (forms VI, VII, VIII, IX and X), amorphous form and solvated forms (ethanolate and methanolate), and processes for their preparation thereof. The Patent also describes a process for preparing sertraline hydrochloride form V by crystallization from various solvents rather than by sublimation.
U.S. Pat. No. 6,495,721 further discloses processes for preparing sertraline hydrochloride form II comprising the steps of dissolving sertraline free base or its mandelate salt in an organic solvent, selected from the group consisting of ethyl acetate, acetone, hexane, t-butyl methyl ether, isopropyl alcohol, n-butanol, t-butanol, isobutanol, and cyclohexane, to form a solution; adding hydrogen chloride to the solution; heating the solution for a time sufficient to induce the formation of sertraline hydrochloride; and isolating sertraline hydrochloride form II.
U.S. Patent Application No. 2001/0041815 A1 (Teva Pharm. Ind.) discloses various polymorphic forms (XI, XII, XIII, XIV, XV and XVI) of sertraline hydrochloride and processes for their preparation.
PCT Patent Publication No. WO 01/32601 A1 (Ciba Specialty Chem.) discloses polymorphic forms of sertraline hydrochloride such as crystalline form (CSC2), crystalline forms of alcohol solvates (ethanol solvate, isopropanol solvate and methanol solvate) and crystalline forms of hydrates (CSC1) and processes for their preparation. The publication also describes, a process for the preparation of the amorphous form of sertraline hydrochloride, and different processes for the preparation of sertraline hydrochloride polymorphic forms I, II, V, and T1.
PCT Patent Publication No. WO 01/32601 A1 further describes a process for the preparation of polymorphic form II of sertraline hydrochloride, wherein a solution of sertraline free amine is seeded with some crystals of polymorphic form II before addition of a solution of hydrogen chloride, or wherein a stirred suspension of sertraline hydrochloride polymorphic form V is stirred with some seeding crystals of sertraline hydrochloride polymorphic form II, or wherein sertraline hydrochloride alcohol solvate is dried at temperatures from 0-30° C. in a high vacuum of less than 1 mbar, or wherein suspensions of sertraline hydrochloride polymorphic forms CSC1, CSC2 or T1 are stirred with some seeding crystals of sertraline hydrochloride polymorphic form II.
U.S. Patent Application No. 2004/0030190 A1 (Teva Pharm. Ind.) describes a reproducible process for preparation of sertraline hydrochloride form II substantially free of crystalline sertraline hydrochloride form I, which comprises, providing a solution of sertraline base, or a solution or slurry of sertraline mandelate, in an organic solvent selected from the group consisting of n-butanol, cyclohexane, ethyl acetate, acetone, hexane, t-butyl methyl ether and dimethylformamide; contacting the solution or the slurry with a flow of gaseous hydrogen chloride at a suitable rate at a temperature within the range of from about 30° C. to about 60° C., during which time sertraline hydrochloride form II forms, wherein the temperature is kept substantially constant during the gas flow; and filtering the sertraline hydrochloride form II at a temperature of from about 30° C. to about 60° C. to obtain sertraline hydrochloride form II substantially free of sertraline hydrochloride form I.
PCT Patent Publication No. WO 2004/041773 A1 (Torrent Research Centre) describes a process for the preparation of sertraline hydrochloride form V by dissolving or suspending sertraline mandelate in a solvent selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, isobutyl alcohol, water or mixtures thereof, reducing the pH of the solution or the suspension with HCl and isolating sertraline hydrochloride form V.
U.S. Patent Application No. 2005/0032906 A1 describes a method of selectively preparing pure sertraline hydrochloride form II, comprising the step of crystallizing sertraline hydrochloride in an acidic solution of an organic solvent selected from the group consisting of n-propanol, n-pentanol, n-hexanol, n-heptanol, n-ocatnol, acetonitrile, 1-methyl-2-piperidone, and mixtures thereof.
According to one object of the present invention is to provide novel and improved processes for preparing highly pure sertraline hydrochloride crystalline form II.
It has been found that the sertraline hydrochloride form II is obtained consistently contrary to the prior art process. The prior art processes require careful control on the temperature during the addition of hydrochloric acid and isolation of sertraline hydrochloride form II. One advantage of the novel process is that no such control is necessary according to the novel process and therefore, the process of the invention is commercially viable.
According to another object of the present invention is to provide a novel process for preparing sertraline hydrochloride crystalline form I.